What do heterozygous deletions in 3p14.1 → p13 and 6q22.1 regions indicate?

Clinical Significance of Heterozygous Deletions at 3p14.1→p13 and 6q22.1

These heterozygous deletions represent pathogenic copy number variants (CNVs) that require immediate genetic counseling, parental testing to determine inheritance pattern, and comprehensive clinical evaluation for neurodevelopmental disorders, congenital anomalies, and behavioral abnormalities.

Interpretation Framework

The microarray findings reveal two distinct heterozygous deletions totaling approximately 5.9 Mb of genomic material. According to ACMG guidelines, such CNVs must be interpreted in the context of:

• Size and gene content of the deleted regions 1
• Known disease associations with these chromosomal regions 1
• Whether deletions are de novo or inherited 1

3p14.1→p13 Deletion (3.6 Mb)

Clinical Associations

The 3p deletion syndrome is a well-characterized disorder with variable penetrance and expressivity 2. This region is associated with:

• Neurodevelopmental manifestations: Developmental delay, intellectual disability (ranging from mild to severe), and autism spectrum disorder 2
• Growth abnormalities: Growth retardation and microcephaly 2
• Dysmorphic features: Ptosis, facial dysmorphism 2
• Behavioral abnormalities: Variable presentation across affected individuals 2

Critical Consideration: Variable Penetrance

A major pitfall in interpreting 3p deletions is their extremely variable penetrance—even within the same family, phenotypes can range from normal to severe 2. One reported family demonstrated a 9 Mb deletion where the mother and daughter were extremely mildly affected while the son had severe clinical features 2. This creates significant challenges for genetic counseling, as the phenotype cannot be reliably predicted based solely on the deletion size or location 2.

Oncological Relevance

The 3p13-p14 region has been implicated in small cell lung carcinoma through loss of heterozygosity studies 3. While this is primarily relevant for somatic mutations in cancer, it underscores the biological importance of genes in this region.

6q22.1 Deletion (2.3 Mb)

Clinical Associations

The 6q22.33 region, when deleted, is associated with a distinct clinical phenotype 4:

• Intellectual disability: Typically mild 4
• Behavioral abnormalities: Consistent finding across affected individuals 4
• Major congenital anomalies: Heart defects, cleft lip and palate 4
• Microcephaly: Frequently observed 4

Genotype-Phenotype Correlation

A family study with six affected members sharing an approximately 1 Mb deletion at 6q22.33 established this as a recognizable microdeletion syndrome 4. The consistency of findings across multiple family members provides stronger evidence for pathogenicity compared to isolated case reports.

Essential Next Steps

Immediate Actions Required

1. Parental testing: Both parents require chromosomal microarray analysis to determine if deletions are de novo or inherited 1

   • De novo deletions carry higher risk of clinical significance
   • Inherited deletions require assessment of the transmitting parent's phenotype
   • Variable penetrance means an apparently unaffected parent may still carry pathogenic CNVs 2

2. Genetic counseling: Mandatory given the complexity of interpretation and variable penetrance 1

3. Confirmatory testing: Consider FISH or alternative methodology to confirm microarray findings, particularly for the larger 3p deletion 1

Clinical Evaluation Protocol

Comprehensive phenotyping should assess:

• Neurodevelopmental: Formal developmental assessment, cognitive testing, evaluation for autism spectrum features 2, 4
• Growth parameters: Serial measurements of height, weight, and head circumference 2, 4
• Cardiac: Echocardiography to exclude structural heart defects 4
• Craniofacial: Examination for cleft palate (including submucous), ptosis, and dysmorphic features 2, 4
• Behavioral: Structured behavioral assessment 4

Critical Pitfalls to Avoid

Do not assume normal parental phenotype excludes inheritance—3p deletions demonstrate extreme variable expressivity where transmitting parents may be minimally or unaffected 2.

Do not rely solely on deletion size to predict severity—smaller deletions can sometimes cause more consistent phenotypes than larger ones, depending on specific gene content 2, 4.

Do not overlook the possibility of unmasking recessive conditions—heterozygous deletions can reveal pathogenic variants on the remaining allele, though this requires additional sequencing if atypical features are present 1.

Recessive Carrier Considerations

While comprehensive reporting of heterozygous recessive carrier status is generally not recommended for microarray findings, laboratories should disclose carrier status when 1:

• Well-characterized recessive disorders with high carrier frequency are involved
• Clinical features are consistent with a recessive condition in the deleted interval

This requires communication with the laboratory if specific recessive conditions are suspected clinically 1.

Ongoing Surveillance

The laboratory report should recommend continued monitoring of medical literature for new genotype-phenotype correlations, though primary responsibility lies with the treating physician 1. Given the evolving understanding of these regions, periodic reassessment may clarify clinical significance over time 1.